1. Field of the Invention
The present invention relates generally to a method and system for concentrating liquid materials. The invention relates more specifically to a method and system for selective removal of one or more components of a temperature-sensitive, multi-component material to form a product having an increased concentration of one or more other components of the material. The present invention further relates to methods and apparatus for processing temperature-sensitive materials, such as blood plasma. In particular, the present invention relates to methods and apparatus for concentrating temperature-sensitive materials, such as blood plasma, and for processing temperature-sensitive materials, such as blood plasma, by cryoprecipitation and/or chromatography.
2. Description of the Background
Plasma is the straw-colored liquid that remains after all of the cellular components of blood have been removed. Consisting of water, electrolytes, various nutrients, immune factors and clotting proteins, plasma has many life-supporting functions. For this reason, plasma is often used for direct transfusion, primarily for cases involving massive blood loss. Many of the individual components of plasma can also be separated and used to treat a variety of diseases, with more than 100 such products now being produced by a multi-billion dollar, worldwide industry.
Thus, there is an immense demand for plasma and plasma products. However, it is not possible to obtain enough material to meet these demands. Although there has been some success in various synthetic techniques, the main source of plasma and plasma products remains the human donor. The overall donation process begins at the collection center. At this point, plasma is either separated from a whole blood donation, or obtained by apheresis, a process that takes only the plasma component of the blood from the donor. Some of the plasma is then used for direct transfusion, and some of the plasma is frozen and then thawed to obtain cold temperature insoluble proteins called cryoprecipitates. Most of the collected plasma, though, is sent to central processing facilities, where it is combined into large vats from which the individual components are then separated.
It has been found desirable for a wide variety of reasons to concentrate one or more components of multi-component materials. For example, in the biomedical field, it is often desired to increase the concentration of materials such as blood constituents, including plasma, immunoglobulins, fibrinogen and/or clotting factors, by removing water and/or other components of the material. In the pharmaceutical field, concentration of drugs or other materials produced in dilute liquid form or in solution is often required to produce an effective or commercially viable product. Food products such as condensed milk are also produced by means of material concentration processes. Material concentration processes also find application in the chemical processing industry, for example, in the removal of water from aqueous solutions, in the removal of organic solvents such as alcohols or alkanes from organic solutions, and the removal of inorganic solvents such as acids from in organic solutions. The concentrated materials may be reconstituted for use by addition of water, saline solution or other materials, or may be used or further processed in concentrated form.
Concentration of a material may be desirable in order to minimize the expense and space requirements related to storage and transportation of the material. For example, the storage and shipment of blood products typically requires expensive refrigeration equipment. The effective capacity of available equipment can be increased by minimizing the volume of the shipped or stored products through material concentration. Increased availability of blood products can save lives in emergency situations such as natural disaster or war, and can provide substantial economic savings in nonemergency applications. Concentration of a material may also be desirable in order to enhance or alter the properties or therapeutic effects of the material. For example, fibrin glue formed by concentration of fibrinogen and other components in blood plasma has found increasing application in the repair of traumatized biological tissue. The concentration of a material also may assist in, or enhance the efficiency of, additional processing of the material. For example, concentration of blood plasma reduces the volume of material to be treated in subsequent decontamination and fractionation steps, thereby reducing the time, expense and equipment requirements for these processes. Material concentration can also enhance the detection of contaminants in a product by increasing the concentration of the contaminants, thereby rendering them more easily detectable.
Previously known material concentration methods have been found to be less than fully successful for many applications. In particular, temperature-sensitive materials are often damaged by known material concentration methods. For example, forced evaporative and distillation methods of concentration, which typically involve the application of heat to the material to be concentrated, can irreversibly denature proteins or otherwise damage the product. Previously known cryoprecipitation methods of concentration, which typically involve freezing the entire quantity of material to be concentrated, can likewise damage temperature-sensitive products. Previously known filtration methods of material concentration typically suffer inefficiencies due to clogging of the filter media, necessitating frequent replacement or cleaning of the filter. Previously known methods and systems for concentrating also suffer from low yields and inefficiencies. For example, pump and line losses often consume a substantial quantity of concentrate in known methods and systems.
Thus it can be seen that a need yet exists for a method and system for concentrating temperature-sensitive materials, which method reduces or eliminates damage to the materials, reduces inefficiencies and increases yield.
It is also known to separate some proteins from blood plasma by cryoprecipitation. The basic principle of cryoprecipitation is that some plasma proteins agglomerate when frozen, and then remain agglomerated when thawed if the temperature is kept sufficiently low, no more than 5xc2x0 C. This technique can thus be used to separate certain proteins, such as Factor VIII, fibrinogen, and von Willebrands factor, from bulk plasma.
Conventional cryoprecipitation techniques, however, suffer from long processing times and poor yields; these limits are indeed some of the prime motivations for the concentrator. It is therefore desirable to develop a cryoprecipitation technology specifically for concentrated plasma.
It is also known to separate and/or purify materials by chromatography. The underlying principle in chromatography is that different materials diffuse through different media at different rates. These differences in rates thus provide a means of separating the various components of complicated mixtures. Such separations are commonly used to identify individual components, such as toxins or other unknowns, and to prepare commercially valuable fractions of known mixtures, such as blood plasma.
In conventional chromatography, the target materials of interest are often organic compounds, which can be in liquid or gaseous forms. The target materials are usually dissolved in a solvent, such as alcohol. The media typically consist of absorbing materials, such as paper or gels.
The overall process amounts to a progression of equilibrium states (K. Hostettmann et al, Preparative Chromatographic Techniques, Springer Verlag, 1998, which is incorporated herein by reference), during which the material to be separated reaches equilibrium with the media and the solvent. The ideal situation is that the flow rates and the relative absorption strengths are balanced well enough to resolve the components.
There are, however, four major factors that act against these ideal conditions. First, the sample may be so large that the starting conditions are not well defined, i.e., part of the sample may be subject to solvent motion, while the rest of the sample sees no treatment, Second, molecular diffusion of the solute under the action of the increasing concentration gradient tends to spread the material in all directions. Third, eddy diffusion due to irregularities in the media can also spread the solute in all directions. Fourth, the resistance of the media to mass transfer can hinder local equilibration. The net effect of these, and other lesser factors, is to spread the components (i.e., the components migrate as broad, possibly overlapping bands as opposed to narrow, resolved bands), thereby reducing the resolution of the system.
To overcome these problems, a number of alternatives are available. These techniques, which include the use of high pressure, rotation, ion exchange, affinity, etc., are often quite successful, but are expensive, complicated, and require long processing times. These problems are particularly severe for high molecular weight components, such as blood plasma proteins.
Nevertheless, chromatography is still the preferred technique for isolating plasma proteins. Compared to the older, but still practiced, Cohn, or cold ethanol, fractionation procedure, chromatography yields greater resolution and less protein damage. For these reasons, new facilities, such as the Australian national unit, are designed for chromatography. Even in this state-of-the-art facility, however, the process is still quite involved and lengthy. For example, a given batch of plasma requires approximately 3 months for complete processing. This very long time is in fact the underlying problem behind recent shortages of various immunoglobulins in the United States, shortages so severe that FDA has relaxed some safety standards.
Thus, there also remains a need for improved chromatography techniques for the separation and/or purification of materials, in particular temperature-sensitive materials such as blood plasma.
Thus, it is one object of the present invention to provide novel systems for processing temperature-sensitive materials.
It is another object of the present invention to provide novel systems for processing blood plasma.
It is another object of the present invention to provide novel systems for concentrating temperature-sensitive materials.
It is another object of the present invention to provide novel systems for concentrating blood plasma.
It is another object of the present invention to provide novel containers for concentrating temperature-sensitive materials.
It is another object of the present invention to provide novel containers for concentrating blood plasma.
It is another object of the present invention to provide novel methods for concentrating temperature-sensitive materials.
It is another object of the present invention to provide novel methods for concentrating blood plasma.
It is another object of the present invention to provide novel apparatus for separating and/or purifying materials by cryoprecipitation.
It is another object of the present invention to provide novel apparatus for separating and/or purifying blood plasma by cryoprecipitation.
It is another object of the present invention to provide novel methods for separating and/or purifying materials by cryoprecipitation.
It is another object of the present invention to provide novel methods for separating and/or purifying blood plasma by cryoprecipitation.
It is another object of the present invention to provide novel apparatus for separating and/or purifying materials by chromatography.
It is another object of the present invention to provide novel apparatus for separating and/or purifying blood plasma by chromatography.
It is another object of the present invention to provide novel methods for separating and/or purifying materials by chromatography.
It is another object of the present invention to provide novel methods for separating and/or purifying blood plasma by chromatography.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventor""s discovery that materials, in particular temperature-sensitive materials such as blood plasma, comprising at least a first component and a second component, may be concentrated to form a product having an increased concentration of one of the first and second components by a method comprising:
(a) cooling at least a portion of the material to a temperature at or below the melting point of the material, said portion containing the first component in liquid phase;
(b) applying ultrasonic energy to at least the cooled portion of the material to form a system comprising a solid phase and a liquid phase, wherein said solid phase comprises said first component; and
(c) collecting said solid phase.
The inventor has also discovered that materials, in particular temperature-sensitive materials such as blood plasma, comprising at least a first component and a second component, may be concentrated to form a product having an increased concentration of one of the first and second components by a system comprising:
(a) a heat transfer device for cooling at least a portion of the material to a temperature at or below the melting point of the material, said portion containing the first component in liquid phase;
(b) an ultrasonic energy source for applying ultrasonic energy to at least the cooled portion of the material to form a system comprising a solid phase and a liquid phase, wherein said solid phase comprises said first component; and
(c) means for collecting said solid phase.
The inventor has also discovered that materials, in particular temperature-sensitive materials such as blood plasma, comprising at least a first component and a second component, may be concentrated to form a product having an increased concentration of one of the first and second components by a container comprising:
(a) a flexible wall portion enclosing a treatment chamber for allowing heat transfer between an external heat transfer device and the material, and allowing ultrasonic energy transmission from an external energy source into the material;
(b) a collection chamber for collecting a removed portion of the first component; and
(c) a product chamber for collecting the product.
The inventor has also discovered that blood plasma concentrates may be processed by a process comprising:
(a) cooling a blood plasma concentrate to a temperature sufficient to form a system comprising a solid phase and a liquid phase; and
(b) collecting said solid phase.
The inventor has also discovered that blood plasma may be processed by a process comprising:
(a) cooling at least a portion of blood plasma and applying ultrasonic energy to at least the cooled portion of said blood plasma, to form a system comprising a solid phase and a liquid phase; and
(c) collecting said solid phase.
The inventor has also discovered that blood plasma concentrates may be processed by using a container comprising:
(a) a flexible wall portion enclosing a treatment chamber for allowing heat transfer between an external heat transfer device and the blood plasma, and allowing ultrasonic energy transmission from an external energy source into the material;
(b) a collection chamber for collecting a liquid phase; and
(c) a product chamber for collecting a solid phase.
The inventor has also discovered that materials, in particular temperature-sensitive materials such as blood plasma, comprising at least a first component and a second component, may be separated into their constituent components and/or purified by a method of chromatography, which comprises:
(a) eluting said material through a stationary phase, while supplying ultrasonic energy ultrasonic energy transmission from an external energy source to the material.
The inventor has further discovered that materials, in particular temperature-sensitive materials such as blood plasma, comprising at least a first component and a second component, may be separated into their constituent components and/or purified by a chromatographic apparatus, which comprises:
(a) a container suitable for eluting said material through a stationary phase and allowing ultrasonic energy transmission from an external energy source into the material; and
(b) an external ultrasonic energy source.
Briefly described, in preferred form, the present invention comprises a method and system for concentrating materials. The method and system of the present invention are particularly suited to the concentration of temperature-sensitive materials, but can also be utilized for the concentration of materials that are not temperature-sensitive. According to the preferred forms of the present invention described in greater detail herein, the method and system of the present invention are applied to concentrate a material comprising at least a first component and a second component. At least a portion of the first component of the material is removed to form a product having an increased concentration of the second component, relative to the concentration of the second component in the initial material. The method and system of the present invention are applicable to concentration of materials including, without limitation: biological materials such as plasma, and/or other blood constituents; pharmaceuticals; chemicals; laboratory testing diagnostics; and food products.
One aspect of the invention provides a method of concentrating a solution or other material comprising at least a first component and a second component, to form a product having an increased concentration of one of the components. The method preferably comprises cooling at least a portion of the material to a temperature at or below the melting point of the solution, said portion containing the first component in liquid phase. The method preferably further comprises applying ultrasonic energy to at least the cooled portion of the material to form crystals of the first component in solid phase. The method preferably also comprises removing the crystals from the material to form the concentrated product. The product can be the material remaining after removal of the crystals and having an increased concentration of the second component or, conversely, can be the removed crystals having an increased concentration of the second component.
In another aspect, the present invention comprises a system for concentrating a material comprising at least a first component and a second component, to form a product having an increased concentration of one of the components. The system preferably includes a heat transfer device for cooling at least a portion of the material to a temperature at or below the melting point of the material, said portion containing the first component in liquid phase. The system preferably also includes an ultrasonic energy source for applying ultrasonic energy to at least the cooled portion of the material to form crystals of the first component in solid phase. The system preferably also includes means for collecting the crystals from the material to form the product. The product can be the material remaining after removal of the crystals and having an increased concentration of the second component or, conversely, can be the removed crystals having an increased concentration of the second component.
In another aspect, the present invention comprises a container for containing a quantity of material during separation of a first component from the material to form a first product having an increased concentration of the first component and a second product having an increased concentration of a second component of the material. The container preferably comprises a flexible wall portion enclosing a treatment chamber for allowing heat transfer between an external heat transfer device and the material, and allowing ultrasonic energy transmission from an external energy source into the material. The container preferably further comprises a collection chamber for collecting a removed portion of the first product. The container preferably also comprises a product chamber for collecting the second product.
The system and method of the present invention may find application in a number of fields, for example: concentration of biological materials such as plasma and other blood constituents; concentration of pharmaceuticals; concentration of chemicals; concentration of laboratory test specimens to increase recognition of low concentration components; and concentration of food products.